The increase in obesity incidence has reached epidemic proportions in the western world and more recently also in developing countries. Obesity is associated with significant co-morbidities such as cardiovascular diseases and Type 2 diabetes. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. Pharmacological intervention is generally less efficacious and associated with side effects. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.
Numerous gastro-intestinal peptide hormones are allegedly involved in the regulation of food intake, being either anorexigenic (e.g. CCK, GLP-1, PYY, secretin) or orexigenic (e.g. ghrelin) [Moran T H: Gut peptides in the control of food intake; Int. J. Obes. (Lond). 2009 33 S7-10]. Recently, oxyntomodulin, a product from the proglucagon gene in intestinal L-cells was shown to induce satiety and reduce body weight in both rodents and humans [Cohen M A et al: Oxyntomodulin suppresses appetite and reduces food intake in humans; J. Clin. Endocrinol. Metab. 2003 88 4696-4701; Dakin C L et al: Oxyntomodulin inhibits food intake in the rat; Endocrinology 2001 142 4244-4250]. Oxyntomodulin is a dual agonist activating both GLP-1 and glucagon receptors, albeit with reduced potency compared to GLP-1 and glucagon, respectively. The anorexigenic effect of oxyntomodulin was previously speculated to be mediated by the GLP-1 receptor, although numerous older studies indicated the involvement of pancreatic glucagon in the control of bodyweight. Two recent papers allegedly show glucagon as an attractive target and demonstrated the power of simultaneous GLP-1/glucagon receptor-targeting by constructing dual agonists and comparing the weight lowering effect in knock-out models [Pocai et al; Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice; Diabetes, 2009, 58, 2258-2266; Day et al; A new GLP-1 co-agonist eliminates obesity in rodents; Nat. Chem. Biol., 2009, 5, 749-757].
One physiological effect of glucagon is to increase blood glucose levels in hypoglycaemic conditions by stimulating glycogenolysis and gluconeogenesis. However, the acute effect of glucagon on blood glucose levels seems to be modest when glucagon is infused at near-physiological levels [Sherwin R S et al: Hyperglucagonemia and blood glucose regulation in normal, obese and diabetic subjects; N. Engl. J. Med. 1976, 294, 455-461]. Glucagon receptor activation has also been shown to increase energy expenditure and decrease food intake in both rodents and humans [Habegger K M et al: The metabolic actions of glucagon revisited; Nat. Rev. Endocrinol. 2010 6 689-697] and these effects are robust and sustained in rodents. The risk of increased blood glucose levels due to glucagon agonism may be counter-acted by appropriate levels of GLP-1 agonism. A GLP-1/glucR co-agonist with a balanced effect on the two receptors may give rise to an improved weight loss compared to a pure GLP-1 agonist without compromising the glucose tolerance. However, there are several obstacles in developing such a co-agonist to a pharmaceutical product, relating to half-life, stability, solubility and receptor activity. For example, if glucagon is used as a starting point for such a co-agonist, the GLP-1 receptor activity needs to be established without destroying the activity at the glucagon receptor. Furthermore, since glucagon is inherently insoluble at neutral pH, it is chemically and physically unstable and its half-life in vivo is only a few minutes.
Several patent applications disclosing different GLP-1/glucagon receptor co-agonists are known in the art, e.g. WO 2008/101017, WO 2010/070255, WO 2012/150503, and WO 2012/169798.
In summary, there are several obstacles in developing such a co-agonist into pharmaceutical products, in particular:
i) Receptor activity—The glucagon and GLP-1 receptor potency and/or binding affinity ratio of the co-agonist should be balanced in order to favour a robust reduction in body weight, without compromising glucose balance;
ii) A protracted profile of action, i.e. an in vivo half-life that allows dosing for example once a day or once a week; and
iii) Acceptable solubility, chemical and physical stability.
When glucagon is used as a starting point for such a co-agonist, the GLP-1 receptor activity and/or affinity needs to be established without destroying the glucagon activity. Native glucagon is inherently insoluble at neutral pH, it is chemically and physically unstable and its half-life in vivo is only a few minutes.